versão impressa ISSN 0103-5053
J. Braz. Chem. Soc. vol.22 no.9 São Paulo set. 2011
College of Chemistry, Wuhan University, 430072, P. R. China
A significant improvement of the chemical yields (up to 88%), stereoselectivity (> 99:1) and enantiomeric excesses (up to 98%) of (L)-proline catalyzed direct asymmetric aldol reaction was found when proline based chiral ionic liquids (CILs) were added as additives. Different ratios of DMSO/H2O as solvent and chiral ionic liquids (CILs) with chiral cations of different chain length were investigated.
Keywords: aldol reaction, asymmetric synthesis, chiral ionic liquids, chiral additive
Melhoras significativas nos rendimentos químicos (até 88%), estereosseletividades (> 99:1) e excessos enantioméricos (até 98%) foram observadas em reações aldólicas assimétricas catalisadas por (L)-prolina, quando líquidos iônicos quirais baseados em prolina (CILs) foram usados como aditivos. Diferentes proporções de DMSO/H2O como solvente, e líquidos iônicos quirais (CILs) com cátions quirais com diferentes comprimentos de cadeia, foram investigados.
Room temperature ionic liquids (RTILs) including chiral ionic liquids (CILs) have received growing attentions both from theoretical research and actual productions due to their tuneable features for various chemical tasks and their advantages as homogeneous support, reaction media, etc.1, 2 Since the first example of chiral ionic liquid reported by Howarth et al.3 in 1997, a large number of CILs bearing chiral cations, anions or seldom both were reported by other groups.4, 5 Previous studies have shown that in many asymmetric reactions the use of CILs as reaction media or catalyst can enhance the yield and/or selectivity significantly.6-8 As most of the asymmetric reactions were carried out using metal/chiral catalysts as chiral sources, which are relatively expensive or environmental unfriendly, searching for a catalyst which is easy to obtain and environmentally benign for the asymmetric reactions is of great significance. In our previous work, a series of (L)-proline based CILs were proved to have the potential to provide a strong chiral environment by 19F NMR study.9 In this article, a series of reactions were carried out to investigate the catalytic properties of these (L)-proline based CILs, and very high chiral selectivity was obtained.
Aldol reaction has been a typical asymmetric reaction used in the search of efficient asymmetric catalyst, especially for environmental friendly and metal-free organic catalyst.10-13 Since CILs used as catalyst in aldol reaction by Luo et al.14 in 2007, many CILs were developed as catalysts for asymmetric reactions. However, in asymmetric reactions where CILs cannot be applied as catalysts, using CILs as the solvent to investigate the chiral inducing capabilities has rarely been reported. Here we chose the asymmetric aldol reactions as our initial focus to examine the applications of CILs in asymmetric reactions. (L)-Proline and its structural analogs were found to be good catalyst for aldol reaction, 15-19 and (L)-proline combined with ILs were also proved to be an efficient catalytic system for asymmetric aldol reactions.20-23 However, a systematic study about the relationship between structure and properties of ionic liquids is of great interest to many researchers.
Results and Discussion
In this work, (L)-proline based CILs (Scheme 1) are used as chiral additives for (L)-proline-catalyzed asymmetric aldol reaction between aldehyde and acetone, and the results are listed in Table 1. CILs alone can not promote this reaction (Table 1, entry 1). Upon addition of (L)-proline even with a slight amount the reactions proceeded at room temperature and gave the aldol product.
The yields were obviously increased with increasing amount of (L)-proline (Table 1, entries 2 to 4). When (L)-proline (30 mol%) and 2b (7.5 mol%) in an acetone mixture of the reactants were used, the reaction proceeded with a superior yield (up to 97%) and a moderate ee value (71%).An obvious decrease of the yield but a slight increase of the ee values can be observed with decreasing amount of (L)-proline. This result is in accordance with that of Jacobsen's catalytic mechanism.25 It can be concluded that the amount of catalyst have a direct relationship with the yield but a slight influence on the reaction selectivity. For the CILs, when the amount of CILs varied from 1 mol% to 7.5 mol%, it was found almost no change in the reaction yield, while the by product due to dehydration increased slightly with the increase of CILs. The ee values definitely increased with the addition of CILs 2b, although very slightly. Using different aromatic aldehyde in the (L)proline catalyzed aldol reaction, adding 2b as additive and as well good yield and selectivity, the enantiomeric excesses can have up to 24% enhancement.
In summary of the results above, the best reaction ratio of catalyst and additives were found to be 30 mol% (L)-proline as catalyst and 7.5 mol% CILs as additives. Based on this founding, all of the following reactions were carried out on these conditions. The recycle ability of the catalyst and CILs were also studied (Table 1, entry 4 f-h). The reaction was taken 24 h, the solvent was evaporated, and resides were extracted with Et2O three times. The combined solution was left for analysis, and resides were dried under vacuum for 3 h for the next cycle. The catalytic activity of the catalyst and CILs can be kept after 3 cycles, with only a slight decrease in ee values. To investigate the generality of the CILs as additives, a series of aromatic aldehyde acceptors were subjected to the same reaction conditions. From the results above, an obvious ee enhancement change can be found when -NO2 was in different positions (entries 4 and 5, entries 9 and 10, entries 14 and 15). In details, the -NO2 in-o and -p position showed better result than that in the -m position. This is mainly due to the positive effect in nucleophilic addition by -NO2 in -o and -p position. Furthermore, other aromatic aldehydes with different substituents at -p positions (entries 16 and 17, entries 18 and 19, entries 20 and 21, entries 27 and 28, entries 29 and 30) were also investigated to validate the results, it can be seen that all of them react well in this catalytic system and almost no significant change in selectivity which reveals that substituents have less effect in the chemical selectivity. As for the CILs, their solubility can be adjusted by altering the alkyl chain. In details, 2 a, 2 b and 2c have good solubility in water while the others with longer chain lengths are better miserable with low polarity solvent. The other two kinds of CILs with different (TG) counter ions also have their own unique proprieties. Thermogravimetric measurement reveals that these CILs have Td (thermal degradation temperature) in the order of BF4 > Br> NO3 -. Although their widely different proprieties were shown by different chain lengths and different counter ions, they showed no significant change both in chemical yields and selectivity. The mechanism is still under investigation. As temperature is an important factor in most of the asymmetric synthesis, lower the temperature (Table 1, entries 6 and 13) in our system showed only a small change in ee values (2% and 5%, respectively).
In addition, the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde in the presence of (L)-proline and 2 in DMSO/H2O solvent was also investigated (Table 2). Similarly, the reactions were carried out using (L)-proline as catalyst with or without CILs. It was very interesting to find that when 10 mol% of CILs was added, the yields, stereo-selectivity and enantiomeric excesses were enhanced significantly. The solvent, which is very important in organic reactions, was optimized by a series of comparison experiments use different ratio of DMSO/H2O (Table 2, entries 1 to 4). It was found that the best results were obtained when the DMSO:H2O = 4:1(Table 2, entry 3). The other CILs were also used as additives in this catalytic system (Table 2, entries 5 to 9).All of them showed superior co-catalytic effect in aldol reactions.
In summary, a novel asymmetric catalytic system with N-substituted pyrrolidine-ionic liquids as chiral additives was developed and their potentials of providing chiral environment by direct asymmetric aldol reaction were demonstrated. This catalytic system can lead to high yields (up to 88%), good stereoselectivities (> 99:1) and superior enantiomeric excesses (up to 98%) for syn-selective aldol reactions. This is the first use of chiral environment as chiral source to lead asymmetric reaction to our knowledge. Further studies on this kind of CILs in other asymmetric reactions are underway in our laboratory.
General procedure for chiral ionic liquid (CILs) synthesis
(L)-Proline (0.1 mol) and 1-bromoalkane (0.3 mol) were mixed in a 100 mL round bottom flask with acetonitrile as solvent at 70 ºC for 2 days in an inert atmosphere. After filtering, the solvent was removed by distillation and the raw products were washed with ether for several times. After purified by column chromatography (CHCl3:EtOH = 20:1), the product was dried under vacuum for 5 h to afford the chiral ionic liquids (CILs) 2a-2f.
2b (0.02 mol) and silver nitrate (or tetrafluoroborate ammonium) (0.02 mol) were stirred at room temperature for 4 h with chloroform as solvent. After filtering, the solvent was distilled off and the desired raw chiral ionic liquids (CILs) 3a and 3b were obtained. After purified by column chromatography (CHCl3:EtOH = 20:1), the product was dried under vacuum for 5 h to afford the final chiral ionic liquids (CILs) 3a and 3b.
Characterization of CILs
1H NMR (300 MHz, D2O) δ 4.19 (dq, 3 H, J 21.3, 7.3), 3.63 (ddd, 1 H, J 11.6, 7.7, 4 .3), 3 .28 (dq, 1 H, J 14.6, 7.3), 3 .17-2.97 (m, 2 H), 2 .29 (ddd, 2 H, J 92.6, 11.4, 6.5), 2 .05-2.00 (m, 1 H), 1 .87 (ddd, 1 H, J 19.6, 14.4, 12.9), 1 .15 (dd, 6H, J 13.2, 7.1). 13C NMR (75 MHz, D2O) δ 12.2, 15.1, 24.2, 30.0, 52.7, 56.4, 65.9, 68.3, 171.4).
1H NMR (300 MHz, D2O) δ 4.42-4.22 (1 H, m), 4 .22-4.03 (2 H, m), 3 .80-3.57 (m, 1 H), 3 .33-2.96 (m, 3 H), 2 .65-2.21 (m, 1 H), 2 .15-1.76 (m, 3 H), 1 .69-1.39 (m, 4 H), 1 .24 (dtd, 4 H, J 14.8, 7.4, 3 .1), 0.76 (td, 5H, J 7.3, 2 .3). 13C NMR (75 MHz, D2O) δ 15.7, 15.8, 21.3, 22.0, 25.2, 30.0, 30.9, 31.0, 32.6, 58.1, 58.5, 69.7, 70.4, 172.3.
1H NMR (300 MHz, CDCl3, TMS) δ 0.78-0.92 (m, 6H, CH3), 1 .22-1.38 (m, 4 H, CH2), 1 .48-1.78 (m, 4 H, CH2), 2 .02-2.26 (m, 3 H, CH2), 2 .42-2.56 (m, 1 H, CH2), 3 .14-3.46 (m, 3 H, NCH2), 3 .84 (s, 1 H, NCH2), 4 .14 (t, 2 H, J 6 Hz, NCH2), 4 .29 (t, 1 H, J 8.4 Hz, CH); 13C NMR (75 MHz, CDCl3, TMS) δ 13.7, 13.8, 19.2, 20.2, 22.5, 28.2, 30.5, 30.5, 55.3, 56.4, 66.9, 67.6, 167.5.
1H NMR (300 MHz, CDCl3, TMS) δ 0.68-0.94 (m, 6H, CH3), 1 .14-1.40 (m, 4 H, CH2), 1 .42-1.80 (m, 4 H, CH2), 1 .97-2.24 (m, 3 H, CH2), 2 .36-2.52 (m, 1 H, CH2), 3 .06-3.40 (m, 3 H, NCH2), 3 .79 (d, 1 H, J 4.5 Hz, NCH2), 4 .12 (t, 2 H, J 6.6 Hz, NCH2), 4 .20-4.32 (m, 1 H, CH); 13C NMR (75 MHz, CDCl3, TMS) δ 13.5, 13.7, 19.1, 19.7, 22.9, 27.9, 28.7, 30.4, 56.1, 56.4, 67.3, 67.4, 168.8.
1H NMR (300 MHz, CDCl3, TMS) δ 0.68-0.84 (m, 6H, CH3), 1 .08-1.36 (m, 12H, CH2), 1 .44-1.88 (m, 4 H, CH2), 2 .02-2.21 (m, 3 H, CH2), 2 .42-2.62 (m, 1 H, CH2), 3 .13-3.40 (m, 3 H, NCH2), 3 .71 (s, 1 H, NCH2), 4 .10 (t, 2 H, J 6.6 Hz, NCH2), 4 .26-4.38 (m, 1 H, CH); 13C NMR (75 MHz, CDCl3, TMS) δ 14.0, 14.0, 22.1, 22.5, 22.6, 25.6, 25.9, 26.7, 28.5, 28.6, 31.3, 31.5, 53.7, 53.7, 64.9, 67.0, 168.1.
1H NMR (300 MHz, CDCl3, TMS) δ 0.72-0.88 (m, 6H, CH3), 1 .05-1.38 (m, 20H, CH2), 1 .52-1.94 (m, 4 H, CH2), 2 .15 (d, 3 H, J 3.9 Hz, CH2), 2 .47-2.63 (m, 1 H, CH2), 3 .13-3.50 (m, 3 H, NCH2), 3 .52-3.74 (m, 1 H, NCH2), 4 .14 (t, 2 H, J 6.9 Hz, NCH2), 4 .23-4.38 (m, 1 H, CH); 13C NMR (75 MHz, CDCl3, TMS) δ 14.2, 14.2, 22.1, 22.7, 22.7, 25.9, 25.9, 27.0, 28.5, 28.5, 29.3, 29.3, 29.3, 29.3, 31.8, 31.9, 53.9, 53.9, 66.9, 66.9, 168.1.
1H NMR (300 MHz, CDCl3, TMS) δ 0.61-0.74 (m, 6H, CH3), 0.96-1.22 (m, 28H, CH2), 1 .40-1.80 (m, 4 H, CH2), 2 .03 (d, 3 H, J 5.4 Hz, CH2), 2 .45 (d, 1 H, J 8.1 Hz, CH2), 3 .18-3.39 (m, 3 H, NCH2), 3 .70 (s, 1 H, NCH2), 4 .00 (t, 2 H, J 6.6 Hz, NCH2), 4 .42-4.34 (m, 1 H, CH); 13C NMR (75 MHz, CDCl3, TMS) δ 14.3, 14.3, 22.0, 22.8, 22.8, 26.0, 26.0, 27.1, 28.6, 28.6, 29.2, 29.2, 29.4, 29.4, 29.7, 29.7, 29.7, 29.7, 32.0, 32.0, 53.3, 53.3, 67.0, 67.0, 167.9.
1H NMR (300 MHz, CDCl3, TMS) δ 0.78-0.97(m, 6H, CH3), 1 .05-1.40(m, 36H, CH2), 1 .48-1.98(m, 4 H, CH2), 1 .98-2.42(s, 3 H, CH2), 2 .60(s, 1 H, CH2), 3 .06-3.38(m, 3 H, NCH2), 3 .64(s, 1 H, NCH2), 4 .04-4.18(m, 3 H, NCH2, CH), 4 .20-4.29(m, 1 H, CH); 13C NMR (75 MHz, CDCl3, TMS) δ 14.3, 14.3, 22.3, 22.8, 22.8, 26.0, 26.0, 26.9, 29.2, 29.2, 29.4, 29.4, 29.4, 29.4, 29.7, 29.7, 29.7, 29.7, 32.0, 32.0, 54.4, 54.4, 67.2, 67.2, 168.1.
General procedure for the aldol reactions
(L)-Proline (30 mol%) and the aromatic aldehyde (1 mmol) were added in the acetone (3 mL); after stirred for 1 min, chiral ionic liquids (CILs) (7.5 mol%) were added and the reaction mixture was stirred at room temperature (25 ºC (± 3 ºC)) for 24 h. The acetone was evaporated, the residue was extracted with diethyl ether (3 mL, three times), separated diethyl ether layer was collected, the residues were dried under vacuum at 40 ºC during 5 h for the next cycle, the collected solvent was evaporated and the residues purified by chromatography on SiO2-column (Petroleum ether:EtOAc = 3:1). All reaction products had the physical constants and NMR spectra in accord with the published data. The petroleum ether used was of boiling range 60-80 ºC. Evaporation of solvent was performed at reduced pressure at 25 (±3) ºC.
Supplementary data are available free of charge at http://jbcs.sbq.org.br as PDF file.
We thank Dr. Zhi-Yong Xue (Wuhan University, Wuhan, China) for help in the HPLC analysis and the National Natural Science Foundation of China (Grant Number: 20972120).
1. Welton, T.; Chem. Rev. 1999,99,2071. [ Links ]
2. Ranke, J.; Stolte, S.; Stormann, R.; Arning, J.; Jastorff, B.; Chem. Rev. 2007,107,2183. [ Links ]
3. Howarth, J.; Hanlon, K.; Fayne, D.; McCormac, P.; Tetrahedron Lett. 1997,38,3097. [ Links ]
4. Earle, M. J.; McCormac, P. B.; Seddon, K. R.; Green Chem. 1999,1,23. [ Links ]
5. Pastre, J. C.; Génisson, Y.; Saffon, N.; Dandurand, J.; Correia, C. R. D.; J. Braz. Chem. Soc. 2010,21,821. [ Links ]
6. Dupont, J.; Suarez, P. A. Z.; Umpierre, A. P.; Souza, R. F.; J. Braz. Chem. Soc. 2000,11,293. [ Links ]
7. Pilissão, C.; Carvalho, P. O.; Nascimento, M. G.; J. Braz. Chem. Soc. 2010, 21,973. [ Links ]
8. Narayanaperumal, S.; Gul, K.; Kawasoko, C. Y.; Singh, D.; Dornelles, L.; Rodrigues, O. E. D.; Braga, A. L.; J. Braz. Chem. Soc. 2010,21,2079. [ Links ]
9. Yu, W.; Zhang, H.; Zhang, L.; Zhou, X.; Aust. J. Chem. 2010, 63,299. [ Links ]
10. Geary, L. M.; Hultin, P. G.; Tetrahedron: Asymmetry 2009, 20,131. [ Links ]
11. Kimball, D. B.; Silks, L. A.; Curr. Org. Chem. 2006,10,1975. [ Links ]
12. North, M.; Pizzato, F.; Villuendas, P.; ChemSusChem 2009,2,862. [ Links ]
13. Mahrwald, R.; Chem. Rev. 1999,99,1095. [ Links ]
14. Luo, S.; Mi, X.; Zhang, L.; Liu, X. H.; Cheng, J. P.; Tetrahedron 2007,63,1923. [ Links ]
15. List, B.; Lerner, R. A.; Barbas, C. F.; J. Am. Chem. Soc. 2000,122,2395. [ Links ]
16. Tang, Z.; Jiang, F.; Yu, L. T.; Cui, X.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.; Wu, Y. D.; J. Am. Chem. Soc. 2003,125,5262. [ Links ]
17. Sato, K.; Kuriyama, M.; Shimazaw, R.; Morimoto, T.; Kakiuchi, K.; Shirai, R.; Tetrahedron Lett. 2008,49,2402. [ Links ]
18. Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F.; J. Am. Chem. Soc. 2001,123,5260. [ Links ]
19. Jia, Y. N.; Wu, F. C.; Ma, X.; Zhu, G. J.; Da, C. S.; Tetrahedron Lett. 2009,50,3059. [ Links ]
20. Guo, H. M.; Niu, H. Y.; Xue, M. X.; Guo, Q. X.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Wang, J. J.; Green. Chem. 2006,8,682. [ Links ]
21. Kotrusz, P.; Kmentova, I.; Gotov, B.; Toma, S.; Solcaniova, E.; Chem. Commun. 2002,2510. [ Links ]
22. Shah, J.; Blumenthal, H.; Yacob, Z.; Liebscher, J.; Adv. Synth. Catal. 2008,350,1267. [ Links ]
23. Reddy, K. R.; Chakrapani, L.; Ramani, T.; Rajasekhar, C. V.; Synth. Commun. 2007,37,4301. [ Links ]
24. Qian, Y.; Zheng, X.; Wang, Y.; Eur. J. Org. Chem. 2010,19,3672. [ Links ]
25. Movassaghi, M.; Jacobsen, E. N.; Science 2002,298,1904. [ Links ]
Submitted: February 21, 2011
Published online: June 21, 2011
FAPESP has sponsored the publication of this article.
1H NMR spectra were recorded on a VARIAN Mercury 300 MHz spectrometer or VARIAN Mercury 600 MHz spectrometer. Chemical shifts are reported in ppm with the TMS as internal standard. The data are reported as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, brs = broad singlet, coupling constant(s) in Hz, integration). 13C NMR spectra were recorded on a VARIAN Mercury 75 MHz or VARIAN Mercury 125 MHz spectrometer. Chemical shifts are reported in ppm with the internal chloroform signal at 77.0 ppm as a standard. Commercially obtained reagents were used without further purification. All reactions were monitored by TLC with silica gel-coated plates. Enantiomeric ratios were determined by HPLC, using a chiralpak AS-H column, a chiralpak AD-H column or a chiralcel OD-H column with hexane and i-PrOH as solvents. The configurations were assigned by comparison of the tR with the reported data.1, 2
Characterization of CILs
Characterization of aldol products
All available reagents and solvents were used without further purification. 1H NMR and 13C NMR spectra were conducted on Mercury VX-300 (Varian 300 MHz) or Unity-Inova 600 (Varian 600 MHz) spectrometer. Chemical shifts are expressed in ppm use TMS as internal standard and coupling constants are reported in Hz.
HPLC conditions for the aldol products
4-Hydroxy-4-(4-nitrophenyl) butan-2-one (5a)
The optical purity was determined by HPLC on chiralpak AS-H column [hexane:2-propanol, 70:30]; flow rate 1.0 mL min-1; λ= 210 nm; major: tR = 12.8 min and minor: tR =16.8 min.
4-Hydroxy-4-(2-nitrophenyl) butan-2-one (5b)
The optical purity was determined by HPLC on chiralpak AS-H column [hexane:2-propanol, 70:30]; flow rate 1.0 mL min-1; λ= 220 nm; minor: tR =8.3 min and major: tR =11.2 min.
4-Hydroxy-4-(3-nitrophenyl) butan-2-one (5c)
The optical purity was determined by HPLC on chiralpak OJ-H column [hexane:2-propanol, 70:30]; flow rate 1.0 mL min-1; λ= 220 nm; major: tR = 10.7 min and minor: tR =12.4 min.
The optical purity was determined by HPLC on chiralpak AD-H column [hexane:2-propanol, 95:5]; flow rate 1.0 mL min-1;λ= 210 nm; major: tR =14.4 min and minor: tR = 16.3 min.
The optical purity was determined by HPLC on chiralpak AS-H column [hexane:2-propanol, 85:15]; flow rate 1.0 mL min-1;λ= 220 nm; major: tR =9.8 min and minor: tR =12.2 min.
The optical purity was determined by HPLC on chiralpak AS-H column [hexane:2-propanol, 70:3]; flow rate 1.0 mL min-1;λ= 220 nm , major: tR =7.1 min and minor: 7.6 min.
The optical purity was determined by HPLC on chiralpak AS-H column [hexane:2-propanol, 80:20]; flow rate 1.0 mL min-1;λ= 220 nm; major: tR = 9.0 min and minor: tR =10.9 min.
The optical purity was determined by HPLC on chiralpak AS-H column [hexane:2-propanol, 70:30]; flow rate 1.0 mL min-1;λ= 220 nm; major: tR =7.0 min and minor: tR =8.1 min.
The optical purity was determined by HPLC on chiralpak AD-H column [hexane:2-propanol, 80:20]; flow rate 0.5 mL min-1;λ= 220 nm; mimor: tR =21.6 min and 22.7, major: tR =24.6 and 31.4 min.
1. Zhou Y.; Shan Z.; Tetrahedron: Asymmetry 2006,17,1671. [ Links ]
2. Jia Y. N.; Wu, F. C.; Ma, X.; Zhu, G. J.; Da, C. S.; Tetrahedron Lett. 2009,50,3059. [ Links ]